Vasodilating and antiarrhythmic activity of heteryl lactones

Article abstract of DOI:10.1016/S0223-5234(99)00206-8

A new series of unsaturated γ- and δ-lactones with pyridyl, quinolyl and nitrophenyl substituents (9, 10) have been synthesized by the condensation of unsaturated methyl lactones with heteryl aldehyde or nitrobenzaldehyde in the base-catalysed aldol react

Full text of DOI:10.1016/S0223-5234(99)00206-8

Eur. J. Med. Chem. 34 (1999) 859−865
©
859
´
1999 Editions scientifiques et médicales Elsevier SAS. All rights reserved
Short communication
Vasodilating and antiarrhythmic activity of heteryl lactones
a
a
a
a
a
Ludmila Leite *, Daina Jansone , Maris Veveris , Helena Cirule , Yuris Popelis ,
b
b
a
Gagik Melikyan , Anna Avetisyan , Edmunds Lukevics
a
Latvian Institute of Organic Synthesis, 21 Aizkraukles Str., LV-1006 Riga, Latvia
Department of Organic Chemistry, Yerevan State University, Yerevan 375049, Armenia
b
(Received 27 October 1998; revised 22 March 1999; accepted 23 March 1999)
Abstract – A new series of unsaturated γ- and δ-lactones with pyridyl, quinolyl and nitrophenyl substituents (9, 10) have been synthesized
by the condensation of unsaturated methyl lactones with heteryl aldehyde or nitrobenzaldehyde in the base-catalysed aldol reaction. The
antiarrhythmic, vasodilating and cardiotonic activities of the synthesized compounds have been studied in vivo and ex vivo. 3-Cyano-5,5-
dimethyl-4-[4'-(4-pyridyl)-1',3'-butadienyl)]-2(5H)-furanone (9e) displayed a significant vasodilating activity. The antiarrhythmic activity of
this compound was higher, but its toxicity lower than that of the procainamide reference drug. Five-membered lactones, particularly
3
-cyano-4-(4-pyridylvinyl)-5,5-dimethyl-2(5H)-furanone (9c), exhibited a remarkable cardiotonic activity. The replacement of a pyridyl
´
substituent by a nitrophenyl group in the pyranone derivative did not change the cardiovascular activity and toxicity. © 1999 Editions
scientifiques et médicales Elsevier SAS
heteryl lactones / antiarrythmic activity / vasodilating activity / cardiotonic activity
1
. Introduction
condensed with aldehydes (1–6) in the presence of NaOH
as a catalyst (figure 1). The unusual reactivity of 2-, 3-
and 4-pyridinecarboxaldehyde with γ- and δ-lactones in a
base-catalysed aldol reaction was shown earlier [3]. It
was found that the synthesis of heteryl lactones 9a–c and
Some of the synthetic and natural compounds contain-
ing an unsaturated five-membered lactone moiety exhibit
a cardiotonic activity [1]. For example, the heart glyco-
sides contain a γ-lactone unit. On the other hand, it
should be noted that the majority of cardiotonic sub-
stances of a novel generation is derived from N-hetero-
cyclic compounds [2]. To determine the role of lactone
units and heteryl substituents as pharmacophores respon-
sible for antiarrhythmic and cardiotonic activity, pyridyl,
quinolyl and nitrophenyl derivatives of unsaturated γ-
and δ-lactones have been prepared and tested in vivo and
ex vivo.
10a–c was accompanied by the formation of the [bis(2-
oxo-3-cyano-5,5-dimethyl-2(5H)-furanyl-4-methyl)-methyl]-
pyridines and [bis(2-oxo-3-cyano-6,6-dimethyl-5,6-di-
hydropyranyl-4-methyl)-methyl]pyridines. To avoid this
addition we used a 2-fold excess of pyridine carboxalde-
hyde. The aldol condensation reaction of aldehydes 4–6
with lactones occurred traditionally and yielded the
corresponding unsaturated derivatives of lactones only.
Lactone 9d was synthesized by the reaction of the
ethoxycarbonyl derivative of methyl furanone 7b with
aldehyde 2. The ester was converted into the sodium salt
by the additional amount of sodium hydroxide. The
reaction of aldehyde 4 with furanone 7a was carried out
in the presence of a catalytic amount of NaOH at room
temperature to give furanone 9e in 21% yield. This was
significantly lower than in the case of aldehyde 3 con-
densation reaction (yield 54%). Raising the temperature
did not increase the yield. In all cases the values of
2. Chemistry
Pyridyl, quinolyl and nitrophenyl derivatives of unsat-
urated γ- and δ-lactones were synthesized according to
the procedure elaborated for the pyridyl derivatives of
furanone and pyranone [3]. Methyl lactones 7 and 8 were
*
Correspondence and reprints

8
60
Figure 1. Synthesis of heteroaryl lactones.
spin-spin coupling constants of the double bond CH=CH
protons (16–17 Hz) indicated that only E- or E,E-isomers
were isolated. The coupling constant of α,â-protons in
chain CH=CH –CH =CH (compound 9e) equalled
The spin-spin coupling constants of the double bond
CH=CH protons in isomers appeared during irradiation
and were 11–13 Hz. This means that the compounds
described in the present article really have
E-configuration. The characteristics of the compounds are
listed in tables I and II.
α
â
10.7 Hz. A similar value of coupling constant (10.4 Hz) is
in agreement with the E-isomer of butadiene [4]. To
obtain an additional proof for the configuration of the
unsaturated synthesized compounds, E-Z photoisomer-
ization caused by UV irradiation of the condensation
products 9a and 10b, d and e was studied. The isomer-
ization process was controlled by electron absorption
spectroscopy. When the solution in ethanol was irradiated
with UV light the intensity of the E-isomer absorption
band at 332–344 nm decreased and a band at 220–285 nm
appeared. According to NMR data the formation of the
E- and Z-isomer mixture caused such changes in spectra.
3. Results and discussion
The proposed cardiovascular activity of newly synthe-
sized compounds was tested in ex vivo experiments on
the isolated rabbit ear artery and in vitro on anaesthetized
laboratory animals. These models were chosen in order
not to miss the compounds with antiarrhythmic, vasodi-
lating and/or cardiotonic activities. Table III summarizes
the data of the antiarrhythmic screening test and acute

8
61
Table I. Reaction conditions and characteristics of compounds 9 d–f and 10 d and e.
a
Compound
Reaction temperature (°C)
Reaction time (h)
Yield (%)
M.p. (°C)
Formula
9
9
9
1
d
e
f
0d
80
80
20
20
4
2
1.5
3
52
21
41
44
275-280
161-163
229-230
222-224
C H NO Na
14
12
4
C H N O
16 14 2
2
2
2
C H N O
18 14 2
C H N O
19 16 2
(dec)
10e
80
1.2
61
224-226
C H N O
16 14 2
4
a
all compounds were analysed for C, H and N.
toxicity obtained for heteryl lactones. The acute toxicity
of the studied compounds was low (LD50 was over
i.v.) also protected against ventricular ectopic beats. So,
we established that the 4-isomer of pyridyl furanone, 9c,
revealed the most pronounced antiarrhythmic activity and
the highest toxicity among all compounds studied (ta-
ble III).
4
00 mg/kg). Only the acute toxicity of compound 9c
(LD50 180 mg/kg) and 9d (200 mg/kg) was comparable
with that of lidocaine (LD50 238 mg/kg). The five-
membered pyridyl lactones 9 a–e had a toxicity similar to
its six-membered analogues except 3- and 4-
pyridylfuranones, the toxicity of which was about 2-fold
higher than that of the substituted pyranones. The re-
placement of pyridyl substituents for a quinolyl group
appeared slightly less toxic (see 9c and f, 10c and d).
Heteryl derivatives 9c, e and 10d injected i.p. in doses
of 15 and 30 mg/kg caused the statistically significant
Almost all of the studied heteryl derivatives of unsat-
urated γ-and δ-lactones caused a more or less marked
relaxation of the previously contracted vessels of the
rabbit ear (table V). Compound 9e exhibited a pro-
nounced vasodilating activity. At the same time, pyridyl
lactone 9a demonstrated two phases of vasodilation/
vasoconstriction but 9b showed a trend towards vasocon-
striction. In this test, six-membered lactones (10a, b and
c) possessed more pronounced vasodilation than five-
membered ones (9a, b and c) and 10a (2-pyridyl) was
more active than 10b and c (3- and 4-isomers). In the
series of pyridyl lactones, we found a tendency of
2-pyridyl substituents to induce a more selective vasodi-
lation in comparison with 3- and 4-pyridyl substituents,
as already stated with calcium channel modulators [5].
Compounds 9e, 9f and 10d induced a significant vasodi-
lation at a concentration of 50 µM (9e being the most
active). This means that these compounds may show a
protection against CaCl -induced arrhythmia. Their ac-
2
tivity was higher but toxicity lower than that of the
reference drug procainamide. The antiarrhythmic activity
was more marked for heteryl lactones with 4-pyridyl
substituent within the furanone series.
Compounds 9b and c were also investigated on anaes-
thetized rats. It was shown (table IV) that these pyridyl
furanones decreased the number of animals with lethal
arrhythmia induced by calcium chloride, but to a lower
extent than lidocaine. Compound 9c (dose = 1 mg/kg,
1
Table II. H NMR chemical shifts (δ, ppm) and spin-spin coupling constants of compounds 9d–f and 10d and e.
Compound
CH=CH (JHH Hz)
Pyrone CH2
Pyrone or
furanone CH3
Phenyl, pyridyl or quinolyl CH (JHH Hz)
9
9
9
d*
7.52, d (16.6); 7.31, d (16.6)
-
-
-
1.54, s
1.65, s
1.75, s
8.74, d, H-2, (1.4); 8.49, dd (4.2, 1.4); 8.00,
dt, H-4, (8.2, 1.4); 7.40, dd, H-5 (8.2, 4.2)
7.34, m, H-3, 5 (6.5); 8.66, m, H-2, 6 (6.1)
e**
f**
6.54, d (15.7); 7.01, d (15.7); 7.14, dd
(10.7, 15.7); 7.55, dd (10.7, 15.7)
7.06, d (16.4); 8.60, d (16.4)
7.65, d, H-3, (4.4); 7.70, m, H-6 (1.4; 6.9;
8
(
.5); 7.82, m, H-7 (1.4; 6.9; 8.5); 8.10, d, H-5
8.5); 8.20, d, H-8 (8.5); 9.01, d, H-2 (4.4)
7.74, m, H-6, (1.2, 7.8, 7.9); 7.86, m, H-7
1
0d*
7.54, d (15.7); 8.42, d (15.7)
3.35, s
2.86, s
1.50, s
1.55, s
(
(
1.2, 7.8, 7.9); 7.93, d, H-3 (4.6); 8.11, d, H-5
7.8); 8.50, d, H-8 (8.0); 9.00, d, H-8 (8.0);
9.00, d, H-2 (4.6)
1
0e**
7.24, d (16.0); 7.59, d (16.0)
7.70-8.35, m, H-4
*
*
DMSO-d6, CDCl3

8
62
Table III. Antiarrhythmic activity and acute toxicity of pyridyl
lactones in mice.
Table IV. Effect of compounds 9b and c on CaCl -induced ar-
2
rhythmia and lethality in rats.
Compound
Dose
Antiarrhythmic Acute toxicity
Compound Dose
(mg/kg, i.v.)
Arrhythmia-scores Survival
(mg/kg, i.p.) activity
LD50
(mg/kg, i.p.)
(M ± SD)
(%)
a
(Y/N)
9b
0.3
3.3 ± 0.4
3.0 ± 0.5
2.8 ± 0.5
2.9 ± 0.5
2.3 ± 0.3*
2.6 ± 0.5
20
40
60*
40
60*
60*
9
9
9
9
9
a
b
c
30
1/5
2/5
1/5
1/5
3/5*
3/5*
1/5
2/5
3/5*
2/5
2/5
1/5
2/5
1/5
2/5
1/5
1/5
1/5
1/5
1/5
3/5*
2/5
1/5
1/5
> 400
1.0
3.0
0.3
1.0
3.0
90
30
> 400
9c
90
15
180 (138.5-234)
200 (153.8-260)
480 (347.8-662.4)
30
Lidocaine
0.3
3.0 ± 0.4
2.1 ± 0.3*
1.8 ± 0.4*
3.8 ± 0.5
20
d
e
15
1
3
-
.0
.0
60*
80*
0
30
15
3
9
0
0
*
P < 0.05 vs. control.
9
1
1
1
1
f
30
> 600
> 400
> 400
> 400
> 600
90
0a
0b
0c
0d
30
90
arterial blood pressure by 18%. At the same time, the
heart rate remained unchanged. The positive inotropic
effect was observed with 9b and 9c at doses of
30
90
30
0.1–2.0 mg/kg (duration of action was slightly shorter for
90
15
3
9
0
0
Table V. Vasodilating activity of the investigated compounds in
rabbit ear artery.
1
0e
30
≥ 600
a
90
Compound
Concentration (µM)
Relaxation (%)
Procainamide 30
1/5
3/5*
2/5
4/5*
0/10
360 (257-504)
9a
10
50
10
50
10
5÷(-3)
10÷(-5)
-2
-8
-3
90
Lidocaine
15
238 (180.3-314)
9b
9c
9e
9f
30
Control
50
-5
a
10
50
10
30*
50*
20
Y, the number of mice protected against CaCl -induced arrhyth-
2
mia; N, total number of experimental animals; *P < 0.05 vs. control
group.
5
10
0
30*
12
10a
5
10
0
27*
15
20
2
15
19
32*
5
strong TXA receptor antagonist activity in the rabbit
blood vessels. The replacement of a 4-pyridyl substituent
of furanone and pyranone (9c, 10c) for a 4-quinolyl group
2
10b
10c
50
10
50
10
(
9f, 10d) patently increased vasodilating properties in
1
1
0d
0e
both cases. Unlike pyridyl derivatives of furanone and
pyranone a nitrophenyl pyranone 10e did not possess the
vasodilating activity.
50
10
50
15
Cardiotonic and vasodilating properties of heteryl lac-
tones were also studied on anaesthetized cats. Maximum
variations in the haemodynamic parameters were regis-
tered about 1–5 min after i.v. administration. The results
obtained are shown in table VI. The compounds 9b and
c possess a significant cardiotonic activity. Compound 9c
Papaverine
1
1
5
-
8
0
0
35*
76*
0
Control
Solvent
-
8
(
dose = 0.5 mg/kg) increased the systolic pressure of the
a
positive value means relaxation; negative one, vasoconstriction;
*P < 0.05 vs. control.
left ventricle by 30%, but dP/dt by 32%, and the mean

8
63
Table VI. Haemodynamic effects. Results are in % (in reference to the control initial value).
a
a
a
a
Compound
Dose (mg/kg, i.v.)
MABP
HR
LVSP
dP/dt
FBF
CBF
9
a
1.0
5
0
-
-
-
12
3
0.1
.0
-20÷5
0
-5
-5
-
6
-
8
-
0
-5÷12
0
9b
0
2
0.1
.5
.0
12
29
3
18
30
0
3÷(-10)
5
-2
0
6
0
23
45
10
30
50
0
26
33
15
32
38
0
10
12
-5
12
15
0
12
22
3
16
20
0
9
1
1
c
0
2
.5
.0
0b
0c
0.1
0
2
0.1
0
2
.5
.0
0
6
0
-3
0
0
0
5
0
5
5
8
0
7
0
5
0
0
3
5
0
6
-3
5
10÷(-5)
.5
.0
5÷(-5)
7
10
5÷(-5)
3
Verapamil (hydrohloride) 0.02
.1
-8
-35
-5
-12
-3
-9
-3
-16
18
45
15
80
0
MABP, mean arterial blood pressure; HR, heart rate; LVSP, left ventricular systolic pressure; dP/dt, left ventricular contractility; FBF, femoral
artery blood flow; CBF, carotid artery blood flow.
a
Haemodynamic parameters are expressed as % change: predrug/postdrug; increase/decrease; positive value means increase; negative one,
decrease.
9
b). However, 9b caused a more marked change in heart
heterocycle. The most active were 4-isomers – 3-cyano-
4-(4-pyridylvinyl)-5,5-dimethyl-2(5H)-furanone 9c and
3-cyano-4-(4-quinolylvinyl)-6,6-dimethyl-(5,6-dihydro)-
2-pyranone 10d. The replacement of a 4-pyridyl substitu-
ent of furanone for a 4-quinolyl group decreased the
antiarrhythmic activity. The similar replacement in the
case of 4-pyridylpyranone caused the activity increase.
rate (within +5 to –10%), compared with 9c. Both pyridyl
furanones 9b and c similarly increased the blood flow in
the femoral and carotid arteries, but this increase was less
than the change in the blood pressure.
The vasodilating effect of a nitrophenyl substituent was
similar to that of a pyridyl one. The vasodilating activity
of pyranone with a nitrophenyl substituent is similar to
that of pyridyl derivatives of furanone and pyranone.
The vasodilating activity depended on the ring size of
the lactone, on the type of heteryl substituent, and on the
position of the substituent in the ring. Six-membered
lactones revealed more pronounced vasodilation than
five-membered ones. 2-Pyridylfuranone and 2-pyridyl-
pyranone demonstrated more marked vasodilation than 3-
and 4-isomers. Besides, this 2-pyridylfuranone also pos-
sessed a vasoconstricting action. The insertion of the
second vinyl group in the aliphatic chain between the
pyridine and lactone rings increased the activity of
pyridyl furanone. Thus 3-cyano-5,5-dimethyl-4-[4'-(4-
pyridyl)-1',3'-butadienyl)]-2(5H)-furanone 9e was the
most active among the compounds studied.
4
. Conclusions
New derivatives of γ- and δ-lactones with pyridyl,
quinolyl and phenyl substituents with E-configuration
were synthesized, their antiarrhythmic, vasodilating and
cardiotonic activities investigated. The acute toxicity of
the compounds studied was low. On the whole, the
five-membered pyridyl lactones had a toxicity similar to
their six-membered analogues (except 3- and
4
-pyridylfuranones). The pyridyl substituents of pyridyl
lactones may be responsible for a higher toxicity in
comparison with quinolyl lactones.
The vasodilating effect of a nitrophenyl substituent is
similar to that of a pyridyl substituent. Cardiotonic
activity is more pronounced for 3- and 4-isomers of
pyridyl furanones. Cardiotonic activity of the correspond-
ing 6-membered lactones is lower.
Pyridyl and quinolyl lactones caused a significant
protection against CaCl -induced arrhythmia. The activ-
2
ity depended on the position of a substituent in the

864
5
5
5
. Experimental protocols
.1. Chemistry
The central ear artery was dissected free at the ear base
and cannulated with polyethylene tube and perfused at a
constant flow from a 4-channel peristaltic pump, Geminy
(
Italy). The perfusion fluid was (mmol): NaCl 136.9; KCl
.68; CaCl 1.8; MgCl 1.05; NaHCO 11.9;
NaH PO 0.42; glucose 5.6 (pH 7.35). Intraluminal in-
.1.1. Methods
2
2
2
3
1
The H NMR spectra were recorded on a Bruker
2
4
WH-90/DS and on an AM-360 (360 MHz) spectrometers
in CDCl or DMSO-d , TMS internal standard. The mass
spectra were obtained on
flow perfusion pressure was measured with a Statham
P23I transducer and recorded on a physiograph DMP-4B
3
6
a
Kratos MS-25
(Narco Bio-System, Huston, USA). As flow remained
chromatograph-mass-spectrometer with an ionizing en-
ergy of 70 eV. Elemental analysis was performed on an
Elemental Analyzer Carlo Erba 1108. Silufol UV-254
plates were used for TLC analysis, eluents – benzene-
acetone 3:1. The melting points were determined on a
Boetius stage and reported without corrections. E-Z
photoisomerization has been studied in ethanol solution
of compounds 9a, 10b, d and e by irradiation with UV
light at 336, 332, 340 and 344 nm respectively for
constant, the alterations in perfusion pressure reflected
changes in the blood vessel resistance, i.e., the degree of
vasoconstriction or relaxation. Vasoconstriction was
caused by intraluminal infusion of U-46619 (thrombox-
ane A receptor agonist). The relaxant responses to the
2
investigated compounds used in different concentrations
were tested. The responses were expressed as a per cent
relaxation (% changes in perfusion pressure) without and
with the investigated compounds or solvent.
45 min. Electronic absorption spectra were recorded on a
Specord UV-VIS spectrometer. Starting furanones 7 and
pyrone 8 were synthesized according to [6] and [7],
respectively. Pyridine aldehydes 1–3 were synthesized by
vapour phase oxidation of methyl pyridines over V O -
5
.2.2. Experiments in vivo
5.2.2.1. Antiarrhythmic activity
2
5
5.2.2.1.1. Antiarrhythmic screening test
MoO catalyst [8]. Starting 1'-(4-pyridyl)acroleine 4 and
3
Antiarrhythmic activity was tested in the experimental
4
-quinolinealdehyde 5 were synthesized according to the
antiarrhythmic screening model on male ICR:JCL mice
19–23 g) as was described earlier [13]. The tested com-
methods described in [9] and [10]. All solvents were of an
analytical grade and used without further purification.
(
pounds or solvents were administered i.p. 15 min before
5
.1.2. General procedure for the synthesis of compounds
i.v. infusion of 2% CaCl solution at a constant rate
(0.02 mL/sec) in a dose of 180 mg/kg. The number of
2
9d–f, 10d and e
A mixture of methyl lactone 7 or 8 (20 mmol), the
animals protected from CaCl -induced lethal arrhythmia
2
aldehyde 4–6 (20 mmol) and NaOH (1.25 mmol) in
MeOH (20 mL) was stirred at room temperature or
refluxed for 1.2–4 h. The condensation products precipi-
tated, and were filtered off after cooling to room tempera-
ture. The precipitates of compounds 9e, f, 10d and e were
recrystallyzed from EtOH.
Compound 9d was synthesized as described above but
when the condensation was completed NaOH (21 mmol)
was added to the cooled mixture. The resulting precipitate
was filtered off, washed with EtOH and air-dried. The
reaction conditions, yields and NMR data are shown in
tables I and II. Procedures for the synthesis of com-
pounds 9a–c and 10a–c and their chemical and physical
data are given in [3].
was defined. The investigated compounds were dissolved
in NaCl 0.9% solution or in dimethyl acetamide and then
diluted with the NaCl 0.9% solution.
5
.2.2.1.2. Calcium chloride-induced arrhythmia.
The experiments were performed according to the
classical method [14]. In brief, Wistar male rats
180–220 g) were anaesthesized with urethan (1.20 mg/
(
kg, i.p.). ECG was registered in II standard lead on a
physiograph DMP-4B (Narco Bio-Systems, Huston,
USA). The 5% CaCl solution was i.v. injected at a dose
2
of 180 mg/kg. Heart rhythm disturbances in scores [15]
and lethality of animals were estimated. Solutions of the
compounds to be tested were administrated into the
femoral vein 3 min prior to CaCl . Every dose was tested
2
5
5
.2. Pharmacological methods
on five rats.
.2.1. Experiments ex vivo
The modified method for the experiments on the
5.2.2.2. Cardiotonic action and hypotensive activity
The method used was described already in [16]. Adult
mongrel male and female cats (3.0–4.2 kg) were anaes-
thesized with α-glucochloralose and urethan (80 and
200 mg/kg, i.p.). The trachea was catheterized and con-
isolated perfused rabbit ear blood vessels was used [11,
2]. Male and female rabbits (2.6–3.3 kg) were eutha-
nazed by i.v. injection of Na pentabarbital (80 mg/kg).
1

8
65
nected to an intermittent positive-pressure respirator
DP-8, SU). Arterial blood pressure from the right femo-
ral artery, left ventricular pressure (electromanometer P
3 ID) and the first derivative (dP/dt) were registered on
acknowledge with gratitude and affection the financial
help they have also received from the Taiho Latvian
Foundation.
(
2
a physiograph DMP-4B (Narco Bio-Systems, Houston,
USA). The blood flow from the left femoral and left
common carotid arteries was measured with an electro-
magnetic flowmeter MFV-1200 (Nihon Kohden, Tokyo,
Japan). The heart rate was calculated using the blood
pressure wave. The solutions of the compounds investi-
gated were injected through a catheter placed in the
femoral vein.
References
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(1987) 595–609.
[2] Yuzhakov S.D., Mastafanova L.I., Mashkovski M.D., Yahontov
L.N., Khim-Farm. Zh. 26 (1992) 4–17; CA 117 (1992) 123832q.
[
3] Jansone D., Leite L., Fleisher M., Popelis J.U., Mazheika I.,
Lukevics E., Melikyan G., Avetisyan A., Chem. Heterocycl. Com-
pds. 34 (1998) 267–270.
[
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5
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were injected i.p. The experimental animals were ob-
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4
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We are grateful to the Latvian Science Council for the
financial support of the programme ‘The Development of
Modern Directions in the Organic Chemistry for
the Production of New Medical Agents’. The authors
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